UK Clinical Pharmacy Association

Estradiol with norethisterone

Brands of this drug

Tablet: Elleste Duet, Elleste Duet Conti, Kliofem, Kliovance, Novofem, Trisequens

Transdermal Patch: Evorel Conti, Evorel Sequi

Issues for surgery

Risk of menopausal symptoms, e.g. hot flushes, if discontinued pre-operatively.

Reduced protection against osteoporosis if discontinued for prolonged period.

For oral preparations only - risk of venous thromboembolism (VTE) if continued.

Advice in the perioperative period

Elective surgery 

Minor surgery

Continue unless there is a risk of prolonged immobilisation – see Major surgery.

Ensure adequate VTE prophylaxis if continued.

Major surgery

Oral preparations: Consider stopping 4-6 weeks before major elective surgery where prolonged immobilisation is likely, particularly vascular and orthopaedic lower limb surgery. See Further information.  

Consider other risk factors that the patient may have that further increase the risk of VTE, e.g. age, weight, previous history of VTE.

Please note, if doses are missed, it may result in breakthrough bleeding in women with a uterus.

Transdermal preparations: continue (but ensure patch sited away from site of operation) – 

see Further information.

Emergency surgery 

Oral preparations: ensure adequate thromboprophylaxis to reduce risk of VTE.

If prolonged immobilisation anticipated, consider discontinuing on admission.

Please note, if doses are missed, it may result in breakthrough bleeding in women with a uterus.

Transdermal preparations: continue (but ensure patch sited away from site of operation) –

– see Further information.

Patients admitted with gallstones (cholelithiasis)

Use of estradiol (with norethisterone) can aggravate gallstones in patients who have a previous history of this condition; bear this in mind for patients admitted with gallstones who are on this medication.

Post-operative advice

If oral preparations are stopped pre-operatively restart after full mobilisation.

Patients undergoing major gynaecological surgery

Review appropriateness of restarting this preparation after major gynaecological surgery.

Interactions with common anaesthetic agents

Sugammadex

Administration of a single bolus dose of sugammadex is predicted to cause a 34% decrease in progestogen exposure. This predicted pharmacokinetic reaction has not been proven clinically, however bear the potential reaction in mind should breakthrough bleeding be reported after concomitant use.

Interactions with other common medicines used in the perioperative period

Dexamethasone

Since oestrogen metabolism can be affected by concomitant use of medicines that affect cytochrome P450 enzymes, specifically CYP3A4; the manufacturers note that concomitant use of an inducer of CYP3A4, such as dexamethasone, may reduce plasma concentrations of oestrogen, with a possible reduction in therapeutic effect and/or changes in uterine bleeding. It is unlikely that use of dexamethasone perioperatively will have a significant effect, but bear the interaction in mind where there is concomitant use of these medications and there is a change in therapeutic effect.

With transdermal HRT administration, the first-pass effect in the liver is avoided and, thus transdermally applied oestrogens HRT may be less affected than oral preparations by enzyme inducers/inhibitors.

Further information

Risk of VTE with oral HRT preparations containing oestrogen

During first pass metabolism in the liver oral HRT preparations containing oestrogen affect the clotting cascade by increasing resistance to protein S and protein C (natural anticoagulants) and increasing fibrinogen, thus increasing the risk of thrombosis. Patients taking oral HRT are at increased risk of VTE compared with non-users. The risk is thought to be greatest in the first year of treatment and also in women with an increased body mass index. The baseline risk of VTE also increases substantially with age.

The risk of VTE varies depending on the oestrogen (and progesterone) content of the preparation. Preparations with conjugated equine oestrogen were associated with higher VTE risk compared to those with estradiol. Higher doses of oestrogen were also associated with higher VTE risk. The highest risk is with preparations containing both conjugated equine oestrogen and medroxyprogesterone acetate and the lowest risk is with estradiol with dydrogesterone.

Risk of VTE with transdermal HRT preparations containing oestrogen

Transdermal administration of oestrogen avoids first pass metabolism and thus has less effect on the coagulation factors than oral HRT. The risk associated with transdermal HRT given at standard therapeutic doses is no greater than the baseline population risk. Since transdermal HRT has little or no impact on coagulation and is not associated with an increased risk of VTE it does not need to be discontinued before elective surgery.

References

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 5th January 2024]

Summary of Product Characteristics – Elleste Duet® (estradiol hemihydrate, norethisterone acetate) 2mg Tablets. Mylan. Accessed via www.medicines.org.uk 05/01/24 [date of revision of the text August 2023]

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 5th January 2024]

National Institute of Health and Clinical Excellence (2019). NG23 Menopause: diagnosis and management. https://www.nice.org.uk/guidance/ng23 [Accessed on 5th January 2024]

Vinogradova, Y. Coupland, C & Hippisley-Cox, J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019; 364: k4810. DOI: 10.1136/bmj.k4810

Summary of Product Characteristics – Evorel Sequi® (estradiol hemihydrate, norethisterone acetate). Theramex UK Limited. Accessed via www.medicines.org.uk 21/01/24 [date of revision of the text May 2022]

Summary of Product Characteristics – Sugammadex 100mg/ml solution for injection. Amarox Limited. Accessed via www.medicines.org.uk 24/01/24 [date of revision of the text September 2023]